Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction.
Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction.
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DOI：
10.1111/acel.13444
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发表时间：
2021-08
期刊：
影响因子：
7.8
通讯作者：
Handa JT
中科院分区：
文献类型：
--
作者：
Cano M;Datta S;Wang L;Liu T;Flores-Bellver M;Sachdeva M;Sinha D;Handa JT
核因子红细胞 2 相关因子 2 (Nrf2) 是一种主要的抗氧化转录因子，在多种与年龄相关的疾病中会减少，包括年龄相关性黄斑变性 (AMD)，这是西方社会老年人失明的最常见原因。由于 Nrf2 的线粒体保护反应尚未得到充分研究，我们研究了其对线粒体的抗氧化反应。在用香烟烟雾提取物（CSE）处理后，对对照和 Nrf2 缺陷的视网膜色素上皮（RPE）细胞进行比较。线粒体抗氧化剂丰度和活性氧（ROS）被量化。通过 TMRM 测定、NADPH、电子传递链活性和 Seahorse 评估线粒体功能。结果在 Nrf2−/− 小鼠中得到证实，并且通过人类眼球的免疫组织化学提供了与 AMD 的相关性。 CSE 诱导线粒体 ROS 损害线粒体功能。特别是 H2O2 的增加，因 Nrf2 缺乏而被放大，并且与线粒体功能障碍的加剧相对应。虽然 Nrf2 不影响线粒体抗氧化剂丰度，但由于 IDH2 和磷酸戊糖途径 (PPP) 基因表达减少导致 NADPH 减少，Nrf2 缺乏会放大 PRX3 的氧化。在严重的 CSE 应激下，内在的细胞凋亡被激活，从而增加细胞死亡。 PPP 成分 TALDO1 免疫标记在人类 AMD 眼球的畸形 RPE 中减少。尽管对线粒体抗氧化剂表达的调节有限，Nrf2 仍会影响 PPP 和 IDH 穿梭活性，从而间接为 TRX2 系统提供 NADPH。这些结果让我们深入了解 Nrf2 缺乏如何影响线粒体抗氧化反应及其在 AMD 病理学中的作用。抗氧化转录因子Nrf2不调节线粒体抗氧化基因的表达，而是调节戊糖磷酸途径和IDH穿梭中的基因，它们共同向线粒体提供NADPH，以便TRX2系统中和H2O2。由于 Nrf2 缺乏（发生在年龄相关性黄斑变性中），吸烟后线粒体会因中和不充分的 H2O2 而受损。
The nuclear factor‐erythroid 2‐related factor‐2 (Nrf2), a major antioxidant transcription factor, is decreased in several age‐related diseases including age‐related macular degeneration (AMD), the most common cause of blindness among the elderly in western society. Since Nrf2’s mito‐protective response is understudied, we investigated its antioxidant response on mitochondria. Control and Nrf2‐deficient retinal pigmented epithelial (RPE) cells were compared after treating with cigarette smoke extract (CSE). Mitochondrial antioxidant abundance and reactive oxygen species (ROS) were quantified. Mitochondrial function was assessed by TMRM assay, NADPH, electron transport chain activity, and Seahorse. Results were corroborated in Nrf2−/− mice and relevance to AMD was provided by immunohistochemistry of human globes. CSE induced mitochondrial ROS to impair mitochondrial function. H2O2 increase in particular, was magnified by Nrf2 deficiency, and corresponded with exaggerated mitochondrial dysfunction. While Nrf2 did not affect mitochondrial antioxidant abundance, oxidized PRX3 was magnified by Nrf2 deficiency due to decreased NADPH from decreased expression of IDH2 and pentose phosphate pathway (PPP) genes. With severe CSE stress, intrinsic apoptosis was activated to increase cell death. PPP component TALDO1 immunolabeling was decreased in dysmorphic RPE of human AMD globes. Despite limited regulation of mitochondrial antioxidant expression, Nrf2 influences PPP and IDH shuttle activity that indirectly supplies NADPH for the TRX2 system. These results provide insight into how Nrf2 deficiency impacts the mitochondrial antioxidant response, and its role in AMD pathobiology. The antioxidant transcription factor Nrf2 does not regulate mitochondrial antioxidant gene expression, but instead genes in the pentose phosphate pathway and the IDH shuttle, which together provide NADPH to the mitochondria for the TRX2 system to neutralize H2O2. With Nrf2 deficiency, which occurs in age‐related macular degeneration, mitochondria become damaged by inadequately neutralized H2O2 after smoking.
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影响因子：
14.9
作者：
Kuosmanen SM;Kansanen E;Kaikkonen MU;Sihvola V;Pulkkinen K;Jyrkkänen HK;Tuoresmäki P;Hartikainen J;Hippeläinen M;Kokki H;Tavi P;Heikkinen S;Levonen AL
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影响因子：
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作者：
Kassoff, A;Kassoff, J;Chew, EY
通讯作者：
Chew, EY
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影响因子：
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作者：
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